3alpha-lower alkanoyloxy-16-lower alkyl-15alpha-bromo-16-pregnene-11, 20-dione and process therefor



United States Patent 3,136,791 Zia-LOWER ALKANOYLOXY-16-LOWER ALKYL- ISa-BROMO-16-PREGNENE-11,20 DIONE AND PROCESS THEREFOR David Taub, Metuchen, Norman L'Wendler, Summit, and Harry L. Slates, Florham Park, N.J., assignors to derck 8: Co., Inc, Rahway, N.J., a corporation of New ersey N Drawing. Filed Feb. 9, 1962, Ser. No. 172,085 4 Claims. (Cl. 260397.45)

This invention is concerned generally with novel steroid compounds and with processes of preparing the same, more particularly, it relates to 16,6-alkyl-11-oxygenated steroids of the pregnane series unsaturated in ring A. It relates also to novel processes for producing l6/3-alkyl steroids as well as l6ot-alkyl steroids.

This application isa'continuation-in-part of copending application, Serial No. ll,982,-filed March 1, 1960, now US. Patent No. 3,053,865, and co-pending application Serial No. 732,114, filed May 1, 1958, both of which are, in turn, divisions of application Serial No. 722,390, filed March 19, 1958.

The new products of our invention may be represented by the following structural formula:

CHzO R where 'R is alkyl, R is hydrogen or acyl, R" is hydroxy or oxygen, and X is hydrogen or halogen. The broken line between carbon atoms 1 and 2 indicates that a double bond may be present in this position.

The l6 8-alkyl steroids produced in accordance with the present invention possess extremely high anti-inflammatory activity, considerably greater than that of the parent steroids, and are especially efiective for the treatment of arthritis and related diseases since they can be administered for their cortisone-like action in extremely low dosage thereby minimizing undesired side effects. The activity of 16 beta-alkyl steroids is especially novel as all previous group substitution modifications of cortical steroids which have resulted in increased anti-infiamma; tory activity have involved introduction of alpha-substituents. a p

In preparing our novel chemical compounds, the starting material utilized may be a 3-substituted-1l-oxygen'ated-16-pregnene-20-one or 3-substituted-11-oxygenated-16- allopregnene-ZO-one which may be identified by the following structural formula wherein X is hydrogen or halogen, Y is alpha or beta hydrogen, Z is oxygen, dioxolane, alpha or beta acyloxy or hydroxy, and R is hydroxy or oxygen as above, with or without a double bond 'at the (6)-p0sition.

3,136,791 Patented June 9, 1964 2 In a preferred embodiment of our invention, 31:- acetoxy-l-pregnene-l1,20-dione which is represented by the following formula:

i=0 ll 1 is utilized as the starting material. However, it is clear to those skilled in the art that other starting materials, such as those described above, may be similarly converted to the desired end products.

It has been found that 3a-acetoxy-16-pregnene-11,20- dione maybe caused to react with diazoalkanes, such as diazomethane and diazoethane to form 3otacetoxy- 16oz,l7a-alkyleneazopregnane-l1,20-dione which has the following structural formula:

where R' is hydrogen or alkyl.

Upon heating 3 a-acetoxy-l6a,16a-alkyleneazopregnane- 11,20-dione, there is formed primarily 3ot-acetoXy-l6- alkyl-l6-pregnene-l1,20-dione which may be represented by the following formula: 1

wherein is alkyl as above.

Heating 3a-acetoxy 16a 17 a alkylene'azopregnane- 11,20-dione also results in the formation of a small quantity of each of the two corresponding isomeric forms namely, the cyclopropane, 3-acetoxy-16a,l7a-alkylenepregnane-11,20-dione, which has the following structural formula: I

wherein R is hydrogen or alkyl and exocyclic olefin, 3- acetoxy-l6-alkylenepregnane-11,20-dione, which may be represented by the formula:

i :0 0: C R!!! where R" is hydrogen or alkyl as above.

Treatment of the above isomeric form, namely the 3-acetoxy-16-alkylenepregnane-11,20-dione with an alkali hydroxide yields 16a-alkyl-3u-hydroxy-16-pregnene-11,20-

dione which has the formula: 20

any

wherein R is alkyl.

Oxidation of 3a-acetoxy-l6-alkyl-16-pregnene-11,20-dione, the major isomer obtained above, with an oxidizing agent such as hydrogen peroxide in the presence of sodium hydroxide or peracids such as peroxytrifiuoroacetic acid results in the formation of 16fl-alkyl-16u,17a-epoxy- 3u-hydroxy-pregnane-11,20-dione which has the structural formula:

wherein R is as above.

Upon treatment of l6fl-alkyl-16a,17a-epoxy-3a-hydroxy-pregnane-l1,20-dione with a strong acid such as perchloric acid there is formed an olefin mixture of 16- alkyl-3a,l7a-dihydroxy-IS-pregnene-l1,20-dione and 16- alkylene 3a,17a-dihydroxy-pregnane-l1,20-dione which may be represented as follows C Ha C H;

wherein R' is hydrogen or alkyl and R is as above.

Treatment of the mixture of l6-alkyl-3a,17u-dihydroxy- 15 pregnene-1l,20-dione and 16-alkylene-3a,17a-dihydroxypregnane-11,20-dione successively with lithium aluminum hydride and sodium metaperiodate results in a mixture of the endocyclic 16-alkyl-3a,llfl-dihydroxy-IS- etiocholene-l7-one and the exocyclic,16-alkylene-3a,11B-

wherein R is hydrogen or alkyl and R is alkyl as above.

Upon treatment of 16B-alkyl-16a,l7a-epoxy-3a-hydroxy pregnane-11,20-dione with hydrogen bromide in acetic acid there is formed 3a-acetoxy-16-alkylene-17uhydroxy-pregnane-l1,20-dione, uncontaminated with the IS-pregnene isomer. There is also produced 3a-acetoxy- 16-a1kyl-l5a-bromo-16-pregnene-11,20-dione which may be represented by the following formula wherein R is alkyl. The 3a-acetoXy-16-alkyl-ISa-bromo- 16-pregnene-11,20-dione thus produced is an important intermediate in the preparation of other active steroids.

The 3a acetoxy-l6-alkyl-15a-bromo-16-pregnene-l1, 20-dione may be reacted with pyridine to form 3a-acetoxy-l6-alky1-14,16-pregnadiene-11,20-rlione which has the formula wherein R is alkyl and R is acetyl; the latter compound may be hydrolyzed to the corresponding 301-01 which has the above formula wherein R is alkyl and R is H.

Hydrogenation of the mixture of l6-alkyl-3a,l7a-dihydroxy-lS-pregnene-l1,20-dione and 16-a1kyl6n6-3a,17ocdihydroxy-pregnane-l1,20-dione with hydrogen in the presence of a hydrogenation catalyst such as palladium on calcium carbonate results in the formation of a mixture of 16a-alkyl-3a,17ot-dihydroxypregnane-11,20-dione and 16/3 alkyl 3a,l7a-dihydroxypregnane-l1,20-dione which may be represented as follows C II;

tar

and

wherein R is as above.

Alternatively, hydrogenation of 16,6-a1ky1-16a,17aepoxy-3a-hydroxypregnane-11,20-dione under acidic conditions produces directly the above mixture of 160t-fl1kY1- 3a,17a-dihydroxypregnane-11,20-dione and 16fl-alkyl-3a, 17a-dihydroxypregnane-1 1,20-dione.

Similarly hydrogenation of the pure l6-alkylene-3a,l7adihydroxypregnane-l1,20-dione resulted in the mixture of 16u-alkyl-3a,17a-dihydroxypregnane-11,20-di0ne and 16fi-alkyl-3 a,17a-dihydrxypregnane-1 1,20-dione.

At this stage, the mixture may be separated into its components by chromatography or fractional crystallization or other means. As hereinafter described the mixture can be processed in the same manner as either of the two components.

Bromination of the above epimeric mixture of 16aalkyl-3u,17a-dihydroxypregnane 11,20 dione and 16B- alkyl-3a,17a-dihydroxypregnane-11,20-di0ne results in the formation of an epimeric mixture of 16ot-alkyl-21-bromo- 301,17u-dihydroxypregnane-11,20-dione and 165-a1kyl-21- bromo-3a,17a-dihydroxypregnane-l1,20-dione which may be represented as follows The above epimeric mixture of l6a-alky1-21-bromo- 3a,l7a-dihydroxypregnane-11,20-dione and 16,8-alky1-2 1- bromo-3a,17a-dihydroXypregnane-11,20-dione may be reacted with potassium acetate to form an epimeric mixture of 160; alkyl 3u,17ez,2l-trihydroxypregnane-l1,20- dione 21-acetate and 16,8-alkyl-3a-17a,21-trihydroxypregnane-l1,20-dione 2l-acetate which may be represented by the following formulae outer (llH oAc 0:0 0 0 ru rd r wherein R is as above.

The above epimeric mixture may be separated by chromatography or crystallization at this stage or carried further.

Reaction of a mixture of 16a-alkyl-3a,17a,21-trihy- .droxy-pregnane-l1,20-dione 2l-acetate and l6B-a1kyl-3u,

1704,21 trihydroxypregnane-l1,2Q-dione ZI-acetate with an oxidizing agent such as N-bromosuccinimide. or chromic acid results in the formation of a mixture of 16a-alkyl-17a,21 dihydroxy-pregnanell1,20-trione 21- acetate and 16fi-a'lkyl-17a,2l-dihydroxy-pregnane-SJ1-20- 6 trione 21-acetate which have the following structural formulae OHsOAc The mixture of 16a-alkyl-l7a,2l-dihydroxypregnaue- 3,11,20-trione ZI-acetate and 16/3-alkyl-l7u,2l-dihydroxypregnane-3,11,20-trione 2l-acetate can be separated by chromatographic procedures.

The l6fl-alkyl-17u,21-dihydroXypregnane-3, l 1,20-trione ill-acetate is reacted with bromine to form 16fl-alkyl-4- CHgOAc bromo-17a,21 dihydroxypregnane-3,11,20-trione 2l-acetate which has the following structural formula CH OAc wherein R is as above.

The 16fi-alkyl-4-bromo-17a,21 dihydroxypregnane-3, 11,20-trior1e 21-acetate obtained above is then reacted with a slurry of semica'rbazide hydrochloride and sodium bicarbonate to form the 3-semicarbazone of -alkyl- 17a,21-dihydroxy 4 pregnene-3,l1,20-trione 2l-acetate which may be represented by the following structural formula wherein R is as above.

The above 3-semicarbazone of l6fi-alkyl-17a,21-dihydroxy-4-pregnene-3,11,20-trione 21-acetate is then reacted With, for example, pyruvic acid in aqueous acetic acid to form 16fi-alkyl-l7a,2l-dihydroxy 4 pregnene-3,11,20 trione ZI-acetate having the following structuralformula CHzOAc wherein R is as above.

The above compound may also be named 16B-alkylcortisone acetate, one of our active end products which possesses effective anti-inflammatory activity.

It has been found that the 16/3-alkyl-17a,2l-dihydroxy- 4-pre gnene-3,11,20-trione 2l-acetate may be converted to the corresponding 2l-ol, namely, 16,B-alkyl-17a,2l-dihydroxy-4-pregnene-3,11,20-trione, by reaction with potassium bicarbonate in aqueous methanol. The latter compound is then reacted with semicarbazide hydrochloride in the presence of dimethylformarnide to form the 3,20- disemicarbazone of 16B-alkyl-l7a,21 dihydroXy-4-pregnene-3,1l,20-trione which has the following structural formula NHZCONHN= i wherein R is alkyl as above.

Reduction of the 3,20-disemicarbazone of 16B-alkyl- 17a,21-dihydroxy-4-pregnenc-3,11,20-trione with sodium boronhydride produces the 3,20-disemicarbazone of 1613- alkyl-l1,6,17a,21-trihydroxy-4-pregnene-3,ZO-dione, which has the following formula:

=NNHCONH,

NHaCONHN= I wherein R is as above.

The 3,20-disemicarbazone of 16fl-alkyl-llfi,17u,2l-tri hydroxy-4-pregnene-3,ZO-dione is reacted with pyruvic acid in aqueous acetic acid to remove the semicarbazone groups at the 3 and 20-positions to form 16,8-alkyl-11B, 17a,21-trihydroxy-4-pregnene-3,ZO-dione which may be chemically represented as follows:

wherein R is as above. The above compound which may be called 16B-alkyl hydrocortisone has been found to exhibit marked and effective activity in the treatment of arthritis.

Acetylation of 16fi-alkyl-11 3,17a,21-trihydroxy-4-pregnene-3,20-dione at the 2l-position is accomplished by reacting this latter compound with acetic anhydride in the presence of pyridine to form l6fl-alkyl-1lB,17a,2l-trihydroxy-4-pregnene-3,20-dione 21-acetate which may be represented as follows:

CHzOAG wherein R is as above.

Other 2l-acylates may be prepared by reacting the 21- alcohol with the appropriate acyl anhydrides.

By reacting 16;8-alkyl-llfl,l7a,2l-trihydroxy-4-pregnene-3,20-dione 2l-acetate with methanesulfonyl chloride in dimethylformamide there is formed 16fi-alkyl-17a,21- dihydroxy-4,9(11)-pregnadiene-3,20-dione 21-acetate of the following structural formula CHzOAC wherein R is as above.

Reacting the latter compound with N-bromo-succinimide forms 16f3-alkyl-9a-bromo-11fl,17a,21-trihydroxy- 4-pregnenc-3,20-dione 21-acetate represented by the formula CHzOAc wherein R is as above.

Reacting the latter compound with sodium methoxide produces 163 alkyl 1lB-epoxy-17a,21-dihydroxy-4- pregnene-3,20-dione having the formula wherein R is as above.

The latter compound is acetylated with acetic anhydride in pyridine and then allowed to react with hydrogen fluoride, to form l6fl-alkyl-9u-fluoro-llp,l7a,2l-trihydroxy- 4-pregnene-3,20-dione 21-acetate of the following structural formula:

CHZOAC ---oH nofli TR pregnadiene-3,20-dione and the corresponding 21-acylates can be prepared by reacting respectively 16fi-alkyl- 17a,21-dihydroxy-11-oXygenated-pregnane-3,ZO-dione 21- acetate and 16B-alkyl-9a-fluoro-17a,21-dihydroxy-ll-oxygenated pregnane-3,20-dione ZI-acetate with bromine to form the corresponding 16fi-alkyl-2,4-dibromo-1704,21-dihydroxy 11 oxygenated-pregnane-3,20-dione 2l-acetate which has the following structural formula:

CHgAG wherein R is as above and X is hydrogen or fluorine and R" is hydroxy or oxygen.

Treatment of these species with dimethyl aniline in dimethylformarnide results in the desired 16-alkyl-17a-,21- dihydroxy-ll-oxygenated-1,4-pregnadiene-3,ZO-dione 21- acetate and 16-,B-alkyl-9a-fluoro-17a,21-dihydroxy-11-oxygenated-l,4-pregnadiene-3,20-dione 21-acetate which may be represented graphically as follows:

wherein R and R are as above.

Alternatively, the 1,4-pregnadiene compounds described above may be prepared from the corresponding 4-pregnene-3-ones by dehydrogenation chemically with selenium dioxide or microbially by means of Bacillus sphaeri- OHS- The following experimental part illustrates in detail some of the compounds which constitute this invention and methods ,for their production. However, this invention is not to be construed as limited thereby in spirit or in scope since it will be apparent to those skilled in the art that many modifications in materials and methods may be made without departing from the invention.

1 0 EXAMPLE 1 Preparation of 3 oz-A cetoxy-I 6 0a,] 7 oc-M ethyl eneazo- Pregnane-J 1,20-Di0ne In a 500 ml. S-neck flask equipped with condenser dropping funnel and nitrogen inlet were placed 20 g. of potassium hydroxide in 90 ml. of water, 100 ml. of methanol and 100 ml. of ether. A solution of 10 g. of N- methyl-N-nitrosotosylamide in 50 ml. of ether was placed in the dropping funnel.

Diazomethane was generated by warming the generation flask to 4045 C. and cautiously adding the N- methyl-N-nitrosotosylamide-ether from the dropping funnel. Nitrogen was utilized to sweep the diazomethane into a solution of 20 g. of 3ot-acetoxy-16-pregnene-11,20- dione in 100 ml. of tetrahydrofuran and 120 ml. ether. The process was continued until the steroid solution remained yellow for several hours. The product, 301- acetoxy-l6m,l7a-methyleneazo-pregnane 11,20 dione largely precipitated from the reaction mixture. After 16 hours, the mixture was filtered, washed with ether and dried in air. Yield 14.24 g., M.P. 186-190 C. (dec.)

emon 2nd crop (on concentration) 4.45 g., M.P. 180-187" 0., 3rd crop, 1.32 g., MP. 18i)190 C. Total usable material 20.01 g.

LR. @59 5.78 sh., 5.82, 6.3%. my? 5.73, 5.82, 6.39 1.

Analysis.-Calculated for C H O N C, 69.55; H, 8.27. Found: C, 69.37; H, 8.01.

EXAMPLE 2 Preparation of 3a-Acetoxy-I6-Methyl-16-Pregnene-11 ,20- Dione; 3 a-A cetoxy-l 6 04,1 7oc-Methylenepregnane-11,20- Dione; 3a-Acet0xy-16-Methylenepregnane-11,20-Di0ne and 3a-Hydr0xy-1 6-Methyl-1 6-Pregnene-1 1,20-Di0ne 37.4 g. of 3a-acetoxy-16a,17ot-methyleneazopregnane- 11,2(l-dione was placed in a 500 ml. round-bottom flask and heated by an oil bath in vacuo (pressure 0.6 mm.). A manometer and 12-liter surge flask Were in the line between the reaction flaskand pump trap. When the bath temperature reached 180 C. the 3a-acetoxy-16u, 17a-methyleneazo-pregnane-11,20-dione began to melt with evolution of nitrogen. The maximum pressure reached was 83 mm. After 10 minutes at ISO-182 C. the melt was cooled. It had iggg 249 E% 191 and was taken up in about m1. of acetone, filtered through diatomaceous earth, concentrated to about 100 ml. and ether slowly added to the boiling solution until crystallization occurred. These crystals of 3aacetoxy-16-rnethyl-16-pregnene-11,20-dione weighed 19.0

g., M.P. l65 168 C.;

15% 234; 2nd crop 5.3 g., MP. -164 C.

E% 211; 3rd crop 5.0 g., M.P. 142-153" 0.

iggp 24.9

max.

Analysis.Calculated' for C H O C, 74.57; H, 8.87. Found: C, 74.30; H, 8.60.

The mother liquors obtained above contained addimax..

'tional 3a-acetoxy-l6-methyl-16-pregnene-1l,20=dione as well as the corresponding isomeric cyclopropane, 30cacetoxy-l6zx,l7a-methylenepregnane 11,20-dione, M.P. 166-l69 C. and exocyclic olefin, 3ot-acetoxy-16a,17a-

methylenepregnane-l1,20-dione which were isolated by chromatography.

The latter, 3a-acetoxy-l6-methylenepregnane-l1,20- dione, was transformed to 3a-hydroxy-16-methyl-16- pregnene-11,20-dione by methanolic potassium hydroxide.

EXAMPLE 3 Preparation of 160a,]7a-Ep0xy-3a-Hydr0xy-16,BMethylpregnane-l 1,20-Dine A solution of 20.0 g. of 3ot-acetoxy-16-methyl-16-pregnene-11,20-dione dissolved in 600 ml. of methanol, was cooled to 18 C., and 80 ml. of 30% hydrogen peroxide followed by 80 ml. of 2.5 N sodium hydroxide were added. Considerable material precipitated from solution, but all redissolved on stirring the reaction mixture at 2530 C. for 40 minutes. The solution was kept at 15-20 C. for 18 hours at which time the ultra-violet maximum at 249 had completely disappeared. Then 600 ml. of saturated salt Water was slowly added, the crystalline precipitate was filtered, washed with water, and dried in air and in vacuum. The 16a,17a-epoxy-3a-hydroxy- 16,8-methylpregnane-11,20-dione thus formed weighed 17.36 g. (93%); M.P. 176l77 C., hexagonal prisms M.P. 178180 C. from acetone-ether.

EXAMPLE 4 Preparation of an Olefin Mixture of 3 0a,] 7ot-Dihydr0xy- 16-Methyl-15-Pregnene-1l ,ZO-Dione and 3 ot-I 7a-Dihydroxy-lo-Methylenepregnane-l1,20-Di0ne To a solution of 2.69 g. of 16a,17a-epoxy-3a-hydroxy- 16/i-methyl-pregnane-11,20-dione in 55 ml. dioxane was added 27 ml. of 2M aqueous perchloric acid. The clear solution was kept at 25-30 C. for 65 hours. Cold water, (175 ml.) was added, the slurry chilled to 8 C. and filtered after 30 minutes. The precipitate, containing a mixture of 3a,17a-dihydroxy-16-methyl-15-pregnene-11,20-dione and 3a,17m-dihydroxy-16-methylenepregnane was washed with water, and dried in air and finally at 50 C. in vacuum. Yield: 2.27 g. (94.5%), M.P. sintering at about 150 C. melting at 158-167 C. The relative proportion of 3a,l7a-dihydroxy-l6-methyl- 15-pregnene-11,20-dione and 3a,17a-dihydroxy-16-methylenepregnane-l1,20-dione is estimated to be of the order of 1:1.

EXAMPLE 5 Preparation of 3a,] lfi-Dihydroxy-I 6-Methyl-15-Eti0ch0- Iene-I 7-One and 3 00,1 1 fi-Dihydroxy-I 6-M ethyleneethiocholane-l 7-One 011013 max.

xg f 232.5, 13% 200; 2.75, 2.8-2.9, 5.80, 5.87, 6.07, 621,1

The conjugate C=-O peaks at 5.80 and 5.87 were of equal intensity indicating the proportions to be 1:1.

1 2 J. Pure 3a,11fi-dihydroxy 16 methylene-etiocholane-l7- one mgg 227, 11% 6.07)

was prepared similarly from pure 3a-acetoxy-16-methylene-17ot-hydroxy-pregnane-11,20-dione obtained by hydrogen bromide opening of the oxide, 3a-acetoxy-16a,17otepoxy-16,8-methylpregnane-11,20-dione (see Example 6).

270; xffgf 2.75, 2.82-2.02, 5.79,

EXAMPLE 6 Preparation of 3 a-A cetoxy-Z 7a-Hydr0xy-1 6 -M ethy lenepregn ane-I 1 ,ZO-Dione and 30t-AClOXy150t-BIOm0'1 6 M ethyl-1 6-Pregnene-1 1,20-Di0ne Analysis.Calcu1ated for: C H 0 Br: C, 61.93; H, 7.14; Br, 17.17. Found: C, 61.83; H, 6.99; Br, 16.89.

From the 50:50 petroleum ether-benzene to benzene eluates there was obtained 1.60 g. 3a-acetoxy- 17u-hydroxy-l6-methylenepregnane 11,20-dione; prisms from acetone-ether M.P. 198200 C.

Analysis.Calculated for: C H O C, 71.61; H, 8.51. Found: C, 71.51; H, 8.07.

EXAMPLE 7 Preparation of 3a-Acet0xy-16-Methyl-14,16- Pregnadiene-l 1 ,ZO-Dione AOILOH 250 m E=9,000;

max

42 mg. of 3oc-acetoxy-15a-bromo-16-methyl-16-pregnene-11,20-dione was dissolved in 2 ml. of pyridine. After 18 hours at 25 C. the mixture was concentrated to dryness in vacuo. The solid residue of 3a-acetoxy-16- methyl-14,16-pregnadiene-11,20-dione was crystallized from ether; prismatic needles M.P. 180l85 C.

xCHKOH 304 mp E=11,000.

EXAMPLE 8 A solution of 3.05 g. (8.47 millimol) of the olefin mixture of 3a,17a dihydroxy 16 methyl 15 pregnene- 11,20-dione and 3a,17ot dihydroxy 16 methylenepregnane-11,20-dione in 80 ml. of methanol was reduced in hydrogen at 1 atmosphere and 25 C. in the presence of 2.0 g. of 25% palladium-calcium carbonate catalyst. Modification of the hydrogenation conditions, pH, solvent, catalyst, etc. alters the isomer ratio significantly. Uptake of the calculated amount of hydrogen was complete in 45 minutes. The mixture was stirred an additional 30 minutes and filtered through diatomaceous earth. The colorless filtrate was taken to dryness and crystallized from ether: a mixture of 3a,17a-dihydroxy-16a-rnethylpregnane-11,20-dione and 3a,17a-dihydroxy-16fl-methylpregnane-11,20-dione was obtained and weighed 3.05 g., sintering at C. melting at 166-182 C.

r z i a t llt 79, 2.95, 5.87/

The product consists of 3a,17a-dihydroxy-1Got-methylpregnane-11,20-dione and 312,170: dihydroxy 16B meth- EXAMPLE 9 Alternate Preparation of 3a,]7et-Dihydr0xy-1owMethylpregnane-1],20 Dione and 30:,170L Dihydroxy 16,8- Methylpregnane-I 1 ,2 O-Dione A solution of 10.0 g. of 16a,l7a-epoxy-3e-hydroxy-16pmethylpregnane-l1,20-dione in 180 ml. of dioxane and 112 ml. of 2M aqueous perchloric acid was prepared. The solution was hydrogenated at 25 C. and 1 atmosphere pressure in the presence of 4.4 g. of 5% palladium on charcoal catalyst. Uptake of one mole of hydrogen was complete in 10 hours. The catalyst was removed by filtration and 300 ml. of 70% saturated sodium chloride was added to the filtrate. After being kept at C. for 30 minutes, the precipitated mixture of 3a,17a-dihydroxyl6a-methylpregnane-l1,20-dione and 30:,17oc-dlhYClIOXY- 16,8-methylpregnane-l1,20-dione was filtered, Washed with water and dried n air. Yield: 9.26 g. Solubility analysis in benzene indicated the product to be 75% 3a,17adihydroxy 16o: methylpregnane 11,20 dione and 25% 3a,17 x-dihydroxy-1GB-methylpregnane-l 1,20-dione.

EXAMPLE 10 Separation of 3 a,1 7a-Dihydr0xy-1 oa-Methylpregnane-l I,

ZO-Dione and 3a,] 7a-Dihydr0xy-1 o d-Methylpregnane- 11,20-Di0ne One gram of the above hydrogenation product, 30,170cdihydroxy-l6ot-methylpregnane-11,20-dione and 3a,l7adihydroxy-l6t3-methylpregnane-11,20-dione, was chromatographed on 100 g. of activated magnesium silicate. The 100% chloroform eluates gave 304,17oz-dll1Ydl0XY-l6zzmethyl-pregnane-l1,20-dione, MP. 168l91 C. identical with authentic material by mixed melting point and intrared spectral comparisons. The methanol-chloroform eluates gave 3a,17a-dihydroxy-16e-methylpregnane- 11,20-dione hexagonal plates from benzene-ethylacetate M.P. 192-197 C.

EXAMPLE 11 Preparation of a Mixture of 3a-Acet0xy 17a-Hydr0xy- 16ot-Methyl-Pregnane-l1,20-Di0ne and 3 a-A cetoxy-l 7o.- H ydroxy-I 6 fi-M ethylpregnane-l 1 ,ZO-Dione To a mixture of 30,17 a-dihydroxy-16oc-methy1pregnane- 11,20-dione and 3a,17ot-dihydroxy-16,8-metl1ylpregnane- 11,20-dione dissolved in pyridine was added acetic anhydride at 20 C. A mixture of 3ot-acetoxy-17ot-hydroxy- 16ix-methylpregnane-11,20-dione and 3ot-acetoxy-17a-hydroxy-16B-methylpregnane-l1,20-dione separated from solution and was recovered. These prisms sintered at 170 C. and melted at 175 -179 C.

This latter compound 1% EXAMPLE 12 Preparation of a Mixture of 21-Br0m0-3ot,17a-Dihydr0xy- 1 6 Ot-M ethyl pregnane-J 1 ,ZO-Dione and 21-Br0m0-3a, J 7a-Dihydroxy-lofl-Methylpregnane-J1,20-Di0ne A solution of 3.50 g. (9.7 millimol) of a mixture of 3a, 17ot-dihydroxy-lfia-methylpregnane-11,20-dione and 3a, 17a-dihydroxy-16t3-methylpregnane-l1,20-dione obtained as above in 40 ml. of chloroform was warmed to 40- 45 C. A solution of 1.76 g. (11 millimol) of bromine in 25 ml. of chloroform was added dropwise to the stirred solution such that the color was not darker than pale yellow (ca. 2 drops/sec., total time1 hour). The nearly colorless solution was cooled to 20 C. and 200 ml. of ether was added. The mixture was extracted with excess cold 5% potassium bicarbonate solution, sodium bisulfite solution, and water and dried'over magnesium sulfate. The colorless residue after removal of solvent, a mixture of 21-bromo-3ot,17a-dihydroxy-16a-methylpregnane-11,20-dione and 21-bromo-3ct,l7a-dihydroxy- 16fi-methylpregnane-11, 20-dione (4.30 g.) gave a positive tetrazolium test. Paper chromatography (benzeneformamide) resolved the material into 2 spots.

EXAMPLE 13 Preparation of a .Mixtnre of 3a,] 7a-21-Trihydr0xy1 6a- Methylpregnane-Z1,20-Di0ne 21 Acetate and 3a,17oc,21 Trihydroxy-lofi-Methylpregnane-l1,20-Di0ne 21-Acerate To 4.30 g. of 2l-blOlnO-3a,I7a-dlhYClIOXY-l6oc-Ine'thylpregnane-11,20-dione and 21-bromo-3a,17ot-dihydroxy- 16B-methylpregnane-11,20-dione in m1. of acetone and 0.10 ml. of acetic acid were added 4.83 g. of anhydrous potassium acetate and 3.85 g. of potassium iodide. The stirred mixture was refluxed for 18 hours and concen trated on the water pump to a small volume. Water was added, the product extracted into ethyl acetate, and the organic extract dried over magnesium sulfate. The product (4.25 g.) was a colorless foam that partly crystallized from acetone-ether to give ca. 30% dense cubes sintering at about C., and melting at 200-213 C., which paper chromatography showed was mainly 3a,17ix, 21-trihydroxy methylpregnane 11,20 dione 21 acetate contaminated with some 3a,17e,21-trihydroxy-1Got-methyI-pregnane-11,20-dione ZI-acetate. The IR. spectrum of this material was similar to that of authentic 30:,17oc, 21 trihydroxy 16cc methylpregnane 11,20 dione 21-acetate in the functional group region but differed significantly in the fingerprint region. Seeding the mother liquors with authentic 3a,17a,21-trihydroxy-16a-methylpregnane-l 1,20-dione 2l-acetate induced crystallization of crude 3 a, 17a,21-trihydroxy-l6ot-methylpregnane-1 1,20-dione 21-acetate which was purified by repeated crystallizaion from acetone-ether and shown to be identical with an authentic sample by mixed M.P., LR. and paper chromatographic comparisons.

EXAMPLE 14 Preparation of J7ot,21-Dihydr0xy-16a-l dethylpregnane-3,

11,20-Tri0ne 21-A cetate and 1 7a,21-Dihydroxy-1 6 ,8- Methylpregnane-3J1,20-Trione 2 1-Acetate To the mixture obtained as above of 3a,].7oc,21-l1ihy- .droxy-16ot-methylpregnane-11,20-dione 21-acetate and 30a,

17oc,21 trihydroxy 16B methylpregnane 11,20 dione ZI-acetate, 4.0 g., in 100 ml. t-butanol and 20 ml. of Water cooled to 1015 C., was added 3.5 gQN-bromo-succinimide. The suspension was stirred at 15 C. until all the N-bromosuccinimide had dissolved (90 minutes). The reaction mixture was kept at 2 C. for about sixteen hours and at 25 C. for 2 hours. Sodium sulfite solution was added to destroy bromine and the mixture concentrated on the water pump to a low volume. A granular precipitate had formed; water was added, the precipitate filtered and Washed with water: 3.30 g., sintering at about C. melting at about 202-212 C. Extraction of the filtrate with ethyl acetate gave .350 g., M.P. 130- 170 C. Since both samples were mixtures by paper chromatography, they were recombined for alumino chromatography. Trituration with 100 ml. hot benzene gave 540 mg. of material M.P. 225235 C. Chromatography of the remainder on neutral alumina (85 g., 100 m1. fractions) gave 1.324 g. of 17a,2l-dihydroxy-16a-methylpregmane-3,11,20-trione 21-acetate, MP. 230 C. from fractions 5-15; 5% CHCl 70% C H Fractions 17-21 (50% CHCl 50% C H to 100% CHCI contained 0.850 g. 17a,21-dihydroxy-16B-methylpregnane-3,11,20- trione 2l-acetate, M.P. 210-213 C. The yield was about 2.0 g. [1.87 g.+ca. .10.20 g. in mixed fraction 16]. The ratio of 17a,21-dihydroxy-16a-methylpregnane-3,11,20- trione 21-acetate to 17a,21-dihydroxy-l6li-methylpregnane-3,ll,20-trione 21-acctate, 2.0: 0.85:7:3, is probably close to the ratio of 3a,17a-dihydroxy-16a-methylpregnane-11,20-dione produced in the hydrogenation.

Pure 17a,2l-dihydroxy-16fi-methylpregnane-3,11,20-trione 21-acetate had the following properties: M.P. 210- 212 C.

Analysis-Calculated for C I-1 C, 68.88; H, 8.19. Found: C, 68.81; H, 7.91.

EXAMPLE 15 Preparation of 4-Bromo-17a,21-Dihydroxy-16[3- Methylpregnarze-3,1 1,20-Tr1'0ne 21-Acetate To a stirred solution of 585 mg. of 17a,21-dihydroxy- 16fi-methylpregnane-3,11,20-trione 21-acetate in 10 ml. of acetic acid and 8 ml. of chloroform kept at 10 C. was added slowly 230 mg. of bromine in 6 ml. of chloroform. After addition was complete, 1.2 g. of sodium acetate in 7 ml. of cold water was added. Additional Water was added and the mixture was extracted with chloroform. The chloroform extract was Washed with dilute potassium bicarbonate, Water and dried over sodium sulfate. The residue was triturated with ether to give 480 mg. of crystalline 4-bromo-17a,21-dihydroxy-16,6-methylpregnane-3, 11,20-trione 21-acetate M.P. 165170 C. dec.

Analysis.Calculated for: C H O Br: Br, 16.08. Found: Br, 15.58.

A second crop of 133 mg. of 4-bromo-17a,21-dihydroxy-16B-methylpregnane-3,11,20-trione 21-acetate was also obtained.

EXAMPLE 16 Preparation of the 3-Semicarbazone of 17a,21-Dihydr0xy- 16B-Met/zyl-4-Pregnene-3,I1 ,20-Tri0ne 21 -Acetate To 583 mg. of 4-bromo-17a,21-dihydroxy-16fl-methylpregnane-3,1 1,20-trione 21-acetate in 20 ml. of acetonitrile under nitrogen was added a slurry of 600 mg. of semicarbazide hydrochloride and 410 mg. sodium bicarbonate in 4 ml. of water. After 2 hours, the acetonitrile was removed in vacuo, water added and 540 mg. of crystalline 3-sernicarbazone of 17a,21-dihydroxy-16B-methyl-4-pregnene-3,11,20-trione 2l-acetate filters, washed with Water and dried.

EXAMPLE 17 Preparation of 17oz,2J-Dihya'r0xy-1ofl-Methylt-Pregnene- 3,11,20-Tri0ne 2l-Acetate 540 mg. of the semicarbazone of 17a,21-dihydroxy-l6[3- methyl-4-pregnene-3,11,20-trione 21-acetate was dissolved in 20 ml. of acetic acid, 1.5 m1. of pyruvic acid and ml. of water. After 18 hours at 25 C., Water was added and the mixture extracted with chloroform. The chloroform extract was washed with aqueous potassium bicarbonate, water and dried over sodium sulfate. Removal of solvent gave crude 17a,2l-dihydroxy-l6B-methyl-4- pregnene-3,ll,20-trione 2l-acetate which was purified by chromatography on neutral alumina and crystallization 1 63 from acetone-ether (hexagonal plates). rial had Ml. 226232 C.,

IDHX. max.

The pure mate- Analysis.-Calculated for C ,,H O C, 69.21; H, 7.75. Found: C, 69.24; H, 7.58.

EXAMPLE 18 Preparation of the 3,20-Disemicarbaz0ne of 170:,21-Dilzydroxy-lofi-Melhyl-4-Pregnene-3,11,20 Trione 21- Acetate To a stirred solution of 500 mg. of 17a,21-dihydroxy- 16fi-methyl-4-pregnene-3,l1,20-trione 21 acetate (prepared as described in Example 17) in 12.5 ml. of methanol and 3 ml. of dimethylformamide kept under nitrogen was added a slurry of 680 mg. of semicarbazide hydrochloride and 370 mg. of sodium bicarbonate in 1 ml. of water. The stirred mixture was refluxed 3 /2 hours and maintained at 45 C. for 17 hours. It was then cooled to 20 C. and 50 ml. of 50% saturated aqueous sodium chloride was added. After 2 hours at 0 C. the precipitate of the 3,20-disemicarbazone of 17a,21-dihydroxy- 16p-methyl-4-pregnene-3,11,20-trione 21-acetate was filtered, washed with water until free of chloride ion and dried in air. Yield over EXAMPLE 19 Preparation of the 3,20-Disemicarbazone of 11 3,17oc,21-

Trilzydroxy-J 6,8-Methyl-4-Pregnene-3,20-Dtone To a stirred solution of 600 mg. of the 3,20-disemicarbazone of 17a,2l-dihydroxy-16fl-methyl-4-pregnene-3, 11,20-trione 2l-acetate in 30 ml. of tetrahydrofuran and 11 ml. of water under nitrogen was added 200 mg. of powdered sodium borohydride. The stirred suspension was refluxed 45 minutes and then cooled to 15 C. Aqueous acetic acid (3 ml. of 30%) was added cautiously and most of the tetrahydrofuran was removed in vacuum. Addition of 5 ml. of methanol and 5 ml. of water induced the product to crystallize. Following addition of 10 ml. of a saturated sodium chloride solution and aging at 0 C. the product 3,20-disemicarbazone of 11fi,17oz,21- trihydroxy-l6B-methyl-4-pregnene-3,20-dione was filtered, washed with water, and dried in air.

EXAMPLE 20 Preparation of 1 1,8,1 704,21-Trihydroxy-J6B-Metl1yl-4- Pregnene-3,20-Dione EXAMPLE 21 Preparation of 115,] 70 21Triltydroxy-16fi-Metl1yl-4- Pregnene-3,20-Dione 21-Acetate The product of the previous Example 20 was acylated at C21 as follows: A solution of mg. of 11[3,l7a, 21-trihydroxy-16l3-methyl-4-pregnene-3,20-dione in 1.0 ml. of pyridine and 0.5 ml. of acetic anhydride was prepared. After 18 hours at 25 C., the solution was taken to dryness in vacuo and the solid residue purified by crystallization in acetone-ether to give l1B,l7a,2l-trihydroxy-l6flmethyl-4-pregnene-3,20-dione ZI-acetate.

dione 21-acetate was purified by chromatography on alumina (20 g.) and elution of the column with benzene. Crystallization of material eluted by benzene gave pure l7a,21-dihydroxy 16B methyl 4,9(11) pregnadiene-3, 20-dione ZI-acetate.

EXAMPLE 23 Preparation of 9a-Bromo-1l/3J 711,21 Trihya'roxy-l 6,8-

M elhyl-4-Pregnene-3,20-Di0ne 21-A aerate To a mixture of 620 mg. of l7a,2l-dihydroxy l6fimethyl-4,9 1 1 )-pregnadiene-3,20-dione 21-acetate and 330 mg. of N-bromosuccinimide in ml. of dioxane and 3.2 ml. of water cooled'to 10 C. was added 1.8 ml. of cold 1M aqueous perchloric acid. The mixture was stirred at C. for 3 hours. Excess N-bromosuccinirm ide was destroyed by addition of aqueous sodium thiosulfate and most of the dioxane was removed in vacuo. About 30 ml. of water was added and crystalline bromohydrin, 9a-bromo-l1,8,17a,21-trihydroxy l6B-methyl 4- pregnene-3,20-dione 21-acetate, was filtered, washed with water, and dried in air.

EXAMPLE 24 Preparali on of 9B,]1B-Epoxy-17a,21-Dihydroxy-16fi M ethyl-4-Pregnene-3,20-Dione 21 A cetate To a stirred solution of 100 mg. of the 9a-bromo-11[5',- 17a,2l-trihydroxy-l6fi-rnethyl-4-pregnene-3',20-dione 21- acetate in 3 ml. of tetrahydrofuran and 1 ml. of methanol under nitrogen was added 1.02 ml. of 0.215 N methanolic sodium methoxide. After 10 minutes at 25 C. 0.2 ml. of acetic acid was added and the methanol removed in vacuo. The residue was acetylated with 1.00 ml. of pyridine and 0.5 ml. of acetic anhydride at 60 C. for 70 minutes. The mixture was taken to dryness in vacuo, Water, added, and the product extracted into chloroform. The residue was crystallized from ether-acetone to give pure 93,1Iii-epoxy-l7a,21-dil1ydroxy-16,3- methyl-4-pregnene-3,ZO-dione ZI-acetate.

EXAMPLE 25 Preparation of 9a-Fluor0-11p31 7a.,21-Trihydr0xy-16fi- M erhyl-4-Pregnene-3,20-Dione 21-Acetate To a solution of 2.00 mg. of 95,11B-epoxy-17a,21-dihydroxy-l6,8-methyl-4-pregnene-3,20-dione 21-acetate in 2 m1. of chloroform and 2 ml. of tetrahydrofuran in a polyethylene bottle at 60 C. was added 2 ml. of a 2:1 (by weight) mixture of anhydrous hydrogen fluoride and tetrahydrofuran. After 4 hours at -10 C. the mixture was cooled to 60" C. and cautiously added to a stirred mixture of 30 ml. of 25% aqueous potassium carbonate and 25 ml. of chloroform kept at S C. The aqueous phase was further extracted with chloroform and the latter phase washed with water and dried over magnesium sulfate. The residue on crystallization from acetone-ether gave pure 9a-fluoro-11fl,17a,21-trihydroxy- 16B-rnethyl-4-pregnene-3,20-dione 21-acetate.

EXAMPLE 26 Preparation of 9a-Fluoro-11 5,1 7a,21-Trihydroxy-1 6B- Methyl-4-Pregnene-3,ZO-Dione To a stirred solution of 110 mg. of 90L-fll101'0-l1;8,17a,- 21-trihydroxy-16fi-methyl-4-pregnene-3,20-dione 21 acetate in 5 ml. of methanol under nitrogen at 25 C. was

18' added 1.00 ml. of 0.26 M methanolic sodium methoxide. After 15 minutes 0.2 ml. of acetic acid in 1 ml. of water was added and the mixture concentrated nearly to dryness. Theresidue was taken up in ethyl acetate and the ethyl acetate solution was washed with water, dried over magnesium sulfate, and concentrated to dryness. Crystallization of the residue from ethyl acetate gave pure 9afluoro-l1/3,17a,2.1trihydroxy-16fi-methyl 4 pregnene- 3,20-dione.

EXAMPLE 27 Preparation of 9a-Chloro-1JBJ7a,21-Trihydr0xy-16fl- M ethyl-4 -Pregnene-3,20-Dione 21-A cetate To a solution of mg. of 9,8,11fi-epoxy-l7a,21-dihydroxy-l6/8-methyl-4-pregnene-3,20 dione 21-acetate in 4 ml. of chloroform was added 5 ml. of concentrated hydrochloric acid. The two-phase mixture was stirred at 25 C. for 1 hour. Adidtion of water and chloroform extraction gave a crude crystalline product which is partly deacetylated. Treatment with 1 ml. of pyridine and 0.5 ml. of acetic anhydride at 25 C. for 18 hours followed by concentration in vacuo and crystallization of the residue from acetone-ether afforded pure 9a-chloro-11 8,- 1711,21 trihydroxy 16B methyl 4 pregnene 3,20- dione 21- acetate.

EXAMPLE 28 Preparation of 2,4-Dibromo-1 7a,21-Dihydr0xy-16;8- Methyl-Pregnene-3,11,20Trione 21 A cetate To a stirred solution of 682 mg. of 17a,21-dihydroxy- 16,B-methylpregnane-3,11,20-trione 21-acetate (prepared as described in Example 17) in 20 ml. of chloroform and 2.25 ml. of acetic acid maintained at 20? C. was added dropwise one-half of a solution of 540 mg. of

' bromine in 2 ml. of chloroform and 3 ml. of acetic acid.

The mixture was warmed to 0 C. and the remainder of the bromine added. Sodium acetate (0.4 g.) in 2 ml. of water was added followed by 20 mg. of sodium sulte. The mixture was concentrated in vacuo to remove the chloroform and 2 0 ml. of water was added. The white powdery precipitate of 2,4-dibromo-17a,21-dihydroxy-16fi-methylpregnane-3,11,20-trione 2l-acetate was filtered, washed with water and dried in air. Yield: 920 mg. M.P. 122130 C. dec.

EXAMPLE 29 Preparation 0 f 1 741,21 Dihya'roxy-16l3-Methyl-l ,4- Pregnadiene-3,11,20-Trione 21-A cetate 3. 8 5 E= ,300 35 2.95.0, 5.75, 5.75, 5.84, 6.01, 6.16, 6.19, 11.20 MS 216 (0:.805).

Analysis.Calculated for C H O C, 69.55; H, 7.30. Found: C, 69.25; H, 7.25.

EXAMPLE 30 Preparation of 1] 711,21Dihydroxy-16 3-Methyl-1,4-Pregnadiene-3,11,20-Trione This compound was obtained by treatment of 1.0 g. of 1711,21 dihydroxy 16B methyl 1,4 pregnadiene- 3,11,20-trione ZI-acetate in 30 ml. of methanol with 1 g. of potassium bicarbonate in 10 ml. of water under nitrogen at reflux temperature for 7 minutes. The mixture was cooled, neutralized with 1 ml. of acetic acid in 10 ml. of water, the methanol removed in vacuo and the product extracted into ethyl acetate. Removal of the ethyl acetate gave crystals (900 mg.) M.P. 195-200 of the desired 17a,21-dihydroxy-16/3-methyl-l,4-pregnadiene-3, 1 1,20-trione.

EXAMPLE 31 Preparation of 11 5,1 7 u,21 -Trihydrxy-1 6 fl-M ethyl-1 ,4- Pregnadiene-3,20-Di0ne 21 -A cetate To 100 mg. of 11B,17a,21-trihydroxy-16fl-methy1-4- pregnene-3,20-dione 2l-acetate in 5 ml. of t-butanol and 0.1 ml. of acetic acid was added 50 mg. of selenium dioxide. The mixture Was refluxed under nitrogen 18 hours, 50 mg. of selenium dioxide was added and the mixture refluxed an additional 24 hours. The mixture was filtered, and the filtrate taken to dryness. The residue was taken up in ethyl acetate and washed successively with aqueous sodium bicarbonate, ammonium sulfide, dilute ammonia water, water, dilute hydrochloric acid and water and dried over magnesium sulfate. It was then treated with activated charcoal and concentrated to dryness. Crystallization of the residue from acetone-ether gave pure 11B,17a,21-trihydroxy-16B-methyl-1,4-pregnadiene-3,20-dione 21-acetate.

EXAMPLE 32 Alternately, the 1,2-dehydrogenation of 11fi,17a,21- trihydroxy-l6 8-methyl-4-pregnene-3,20-dione 21-acetate can be carried out microbiologically by means of Bacil Ius sphaericus to yield 11fi,17a,21-trihydroxy-16B-methyl- 1,4-pregnadiene-3,20-dione, which on acetylation with acetic anhydride-pyridine gives 1l/9,17a,21-trihydroxy- 16B-methyl-1,4-pregnadiene-3,20-di0ne 21-acetate.

20 EXAMPLE 33 Preparation of 9a-Flu0r0-11BJ 7a,21-Trihydr0xy-16fl- Methyl-1,4-Pregnadiene-3,20-Di0ne 21 -A cetate In a similar manner, mg. of 9a-flu01'0-11B,17a,21- trihydroxy-16,8-methy1-4-pregnene-3,20-dione 21-acetate was treated with selenium dioxide to produce the corresponding 9a fluoro 11fi,17a,21 trihydroxy 16B- methyl 1,4 pregnadiene 3,20 dione 21-acetate. Alternately, Bacillus sphaerious may be utilized. The 21- alcohol was prepared from the 21-acetate as in Example 26 or Example 30.

Various changes and modifications may be made in the present invention, certain preferred embodiments of which are herein disclosed, without departing from the scope thereof; to the extent that these changes and modifications are within the scope of the appended claims, they are to be considered a part of this invention.

We claim:

1. The process which comprises reacting 3OL-1OWGI' a1- kanoy1oxy-16-lower alkyl-16a,17a-epoxy-pregnane-11,20- dione with hydrogen bromide to form a mixture of 30:- lower alkanoyloxy-16-lower alkyl-15a-bromo-16-pregnene-dlJO-dione, and 16-lower alkylene-3a-lower alkanoyloxy-17a-hydr0xy-pregnane-1 1,20-dione.

2. Bot-lower a1kanoyloxy-l6-lower alkyl-15a-br0mo- 16-pregnene-11,20-dione.

3. The process which comprises reacting 3a-lower a1- kanoyloxy 16 methyl 16a,17u epoxy pregnanc- 11,20-dione with hydrogen bromide to form a mixture of 3a-lower alkanoyloxy-16-methy1-15a-bromo-16-pregnene- 11,20-dione, and 16-methyl-3a-lower alkan0yloxy-17ahydroxy-pregnane-l 1,20-dione.

4. 3m acetoxy 16 methyl 15a bromo 16 pregnene-11,20-dione.

References Cited in the file of this patent UNITED STATES PATENTS 3,053,865 Taub et a1. Sept. 11, 1962 

1. THE PROCESS WHICH COMPRISES REACTING 3A-LOWER ALKANOYLOXY-16-LOWER ALKYL-16A,17A-EPOXY-PREGANA-11,20DIONE WITH HYDROGEN BROMIDE TO FORM A MIXTURE OF 3ALOWER ALKANOYLOXY-16-LOWER ALKYL-15A-BROMO-16-PREGNENE-11,20-DIONE, AND 16-LOWER ALKYLENE -3A-LOWER; ALKANOYLOXY-17A-HYDROXY-PREGANE-11,20-DIONE.
 2. 3A-LOWER ALKANOYLOXY-16-LOWER ALKYL-15A-BROMO16-PREGNENE-11,20 DIONE. 